Influenza is a type of acute infection caused by an influenza virus. The incubation period from infection with the influenza virus to onset of influenza is usually one to two days. The onset is accompanied by the following symptoms, for example: a fever of 38 degrees or higher, systemic symptoms (such as general malaise, headache, joint pain, and muscle pain), sore throat, cough, and nasal discharge. In general, recovery takes one week or less. Influenza may lead to complications such as pneumonia and bronchitis, which may become severe and result in death, in the case of onset of influenza in people such as elderly people, infants, pregnant women, patients with chronic respiratory disease, patients with chronic cardiovascular disease, diabetic patients, and chronic renal failure patients. In addition, influenza intensively occurs in epidemics in a short period of time, and thus sometimes affects the society and causes an economic loss.
Administration of influenza vaccine is the most effective method of preventing influenza from becoming severe. An influenza vaccine preparation is usually a liquid preparation used as an injectable drug or nasal preparation.
For distribution of a liquid preparation of influenza vaccine, temperature control (so-called a cold chain) is required throughout the entire process of distribution and storage in order to prevent deactivaton of the influenza vaccine. Although the epidemic season is different depending on the region, influenza is pandemic, and it is difficult to distribute the preparation while maintaining the activity of the influenza vaccine antigen in the countries and regions where the temperature control is difficult.
Currently available influenza vaccines are roughly divided into live attenuated influenza vaccines and inactivated influenza vaccines. Further, inactivated influenza vaccines are classified into the following three groups: (1) whole virus inactivated with formalin or the like; (2) split vaccine obtained by disrupting virus particles with an organic solvent or a surfactant and solubilizing lipid envelopes; and (3) subunit vaccine obtained by purifying hemagglutinin (HA) and neuraminidase (NA). Among these, two types of vaccines, i.e., split vaccines and subunit vaccines, are currently available as commercial influenza vaccines. Both of these vaccines are usually prepared by disrupting virus particles with an organic solvent or a surfactant and isolating or purifying viral proteins depending on the type.
However, while influenza virus particles have a high sterol content and are usually stable, problems such as a time-dependent decrease in the titer occur during a storage period in the case where the vaccine is obtained by disrupting virus particles, removing lipid substances from the virus particles, and isolating or purifying viral proteins. As described above, since the split vaccine and the subunit vaccine are not necessarily stable, temperature control is required throughout the entire process of distribution and storage in order to maintain the activity of the influenza vaccine antigen.
As a method of overcoming the above-described drawback of the liquid preparation of influenza vaccine, an attempt has been made to produce a preparation in dry form.
For example, Patent Literature 1 discloses production of particles by spray-drying an influenza virus together with a thickener. Patent Literature 2 discloses production of a powder by spray-drying an antigen together with various additives. Patent Literature 3 discloses a pharmaceutical composition in which an attenuated influenza virus as a live influenza vaccine is stabilized by lyophilizing a vaccine solution containing sucrose as a stabilizer, dextran as a bonding agent, and xanthan gum as an excipient. Patent Literature 4 discloses a pharmaceutical composition in which an influenza HA vaccine is stabilized by lyophilizing a vaccine solution containing a hydrophobic amino acid (phenylalanine, valine, leucine, and isoleucine) and arginine hydrochloride as stabilizers.
A seasonal influenza HA vaccine is a vaccine reformulated annually for specific strains, and a mixed type vaccine such as a trivalent vaccine (two strains of type A and one strain of type B) or a tetravalent vaccine (two strains of type A and two strains of type B) is a mainstream vaccine. However, since the amino acid sequence or conformation is different according to the viral type, it is difficult to stably store a pharmaceutical composition containing plural influenza HA vaccines by conventional vaccine formulation techniques.